Experimental Models of Diabetes

John H. McNeill, John H. McNeill

• Publisher: Routledge
• Year: 2018
• ISBN:
  9781351449205
• Edition: 1
• Topic: Medicina
• Subtopic: Teoría, práctica y referencia médicas

An extremely useful text for research Internationally renowned experts describe the models, provide data obtained with those models, and discuss the relative usefulness of models in relation to the diabetic syndrome in humans. The first section examines the most widely used model, the streptozotocin (STZ) rat, condensing a massive quantity of literature to present both the general effects of of STZ diabetes and the effects on individual organ systems. The second section discusses less well-known and more recent diabetic models, such as the BB rat, the NOD mouse and Zucker and Zucker Diabetic Fatty rat models.
Genetic models of insulin dependent diabetes mellitus (IDDM) are examined and compared to chemically induced IDDM models.

Section I

The Streptozotocin-Induced Diabetic Rat

1

Streptozotocin-Induced Diabetes: Induction, Mechanism(s), and Dose Dependency

Brian Rodrigues, Patrick Poucheret, Mary L. Battell, and John H. McNeill

CONTENTS

1.1 Introduction

1.1.1 Diabetes

1.1.2 Classification of Diabetes

1.1.2.1 Type I Diabetes

1.1.2.2 Type II Diabetes

1.2 Animal Models of Diabetes

1.2.1 NIDDM Animal Models

1.2.2 IDDM Animal Models

1.3 Streptozotocin Diabetes

1.3.1 Mechanism of the Diabetogenic Effect of STZ

1.4 Administration of STZ

1.4.1 Relationship of STZ Dose to Severity of Diabetes

1.4.2 Routes of Administration of STZ

1.4.3 STZ Diabetes in Female Rats

1.4.4 Effect of Age on Diabetogenic Action of STZ

1.4.5 Preparation of STZ

1.4.6 Susceptibility of Different Strains of Rats to STZ Diabetes

1.5 Care of STZ Diabetic Rats

1.6 Conclusion

Acknowledgments

References

1.1 Introduction

1.1.1 Diabetes

The pancreas is an organ composed of exocrine (∼98%) and endocrine (∼2%) cells. The islets of Langerhans are clusters of endocrine tissue that are dispersed throughout the exocrine pancreas. There are four major cell types present within mammalian islets. These are β-cells (insulin producing), α-cells (glucagon producing), δ-cells (somatostatin producing), and PP-cells (pancreatic polypeptide). The critical role of the pancreas in diabetes was not realized until it was discovered that complete removal of this organ resulted in hyperglycemia in dogs.¹ Subsequently, the Nobel prize was awarded to researchers who discovered that insulin from pancreatic extracts dramatically reduced hyperglycemia in pancreatectomized dogs.² Gepts³ later demonstrated specific β-cell abnormalities and inflammmatory cells in the islets of Langerhans in patients with recently diagnosed insulin-dependent diabetes, and, using quantitative morphometry, it was found that Type I diabetes was associated with a specific and complete loss of pancreatic β-cells.⁴

TABLE 1.1
Characteristic Features of Diabetes Subtypes

Characteristics	Type I (IDDM)	Type II (NIDDM)
Symptoms	Polyuria, polydipsia, fatigue, weight loss	Often asymptomatic in early years but may present with Type I symptoms especially in advanced stages
Age	<35 (common in youth)	>35 (frequent in adults)
Onset	Abrupt (days to weeks)	Weeks to months to years
Nutritional status	Undernourished	Majority are overweight
Ketosis	Prone	Resistant
Insulin	Mandatory	Required in <30%
Diet	Mandatory	Controls 30 to 50% cases
Ji-Cells	None (complete islet cell loss)	Varies
Islet cell antibodies	Yes	No
Family history	+in 10%	+in 30%
(Identical twins)	∼50% concordance	∼100% concordance

Glucose stimulates the β-cells of the islets to release insulin, which then promotes glucose uptake and storage in various tissues. Considering these effects, hyperglycemia was believed to be due to insulin deficiency and hypoglycemia due to insulin excess. However, with the advent of insulin radioimmunoassays, it became apparent that the majority of patients with hyperglycemia were not completely insulin dependent and, in fact, had normal or even elevated concentrations of circulating insulin. Thus, diabetes mellitus is the name given to a multiple group of disorders with different etiologies. It is characterized by derangements in carbohydrate, protein, and fat metabolism caused by the complete or relative insufficiency of insulin secretion and/or insulin action. These aberrations account for the acute (fatigue, polyuria, polydipsia, etc.) as well as chronic (retinopathy, neuropathy, nephropathy, peripheral vascular disease, heart failure, etc.) complications of the disease.⁵

1.1.2 Classification of Diabetes

The classification of diabetes is based principally upon clinical symptoms and, when possible, on more specific etiologic characterization. Table 1.1 summarizes the two major types of diabetes: (1) diabetes associated with insulin-deficiency (Type I, insulin-dependent, IDDM; 5 to 10% of all cases) and (2) diabetes associated with insulin resistance (Type II, noninsulin-dependent, NIDDM; 90 to 95% of all cases). Other types of diabetes include gestational diabetes, impaired glucose tolerance, and diabetes resulting from other conditions or syndromes.⁶

1.1.2.1 Type I Diabetes

This disease is associated with a specific and complete loss of pancreatic β-cells, leaving islets composed of an increased number of α, δ, and PP cells. Thus, Type I diabetes can be thought of as a specific β-cytectomy, a phenomenon mimicked in animals with the use of chemical agents like alloxan or streptozotocin. Autoimmune destruction of pancreatic β-cells has been suggested to be the most common cause of IDDM. Although the factors that initiate this autoimmune response are not completely understood, it is more frequent in patients with certain human leukocyte antigen tissue types. Other initiating factors include viruses (i.e., Coxsackie B₄)7 and chemical toxins. Less common causes of IDDM are conditions that result in a reduction in the mass of islet cell tissue, such as may occur with several types of pancreatitis, pancreatic carcinoma, and pancreatectomy.

1.1.2.2 Type II Diabetes

Patients with NIDDM represent 90 to 95% of the diabetic population. Between 60 and 90% of those having NIDDM are obese,⁸ often exhibiting hyperinsulinemia and associated insulin resistance. Although the primary causes of the disease have not been identified at the molecular level, current research strongly suggests that this disease arises as a consequence of (1) failure of insulin action due to abnormalities at the cell surface (decreased affinity of the receptors for insulin) or within the cell (post-receptor defects) and (2) deficiency in insulin secretion or (3) a combination of these processes.⁹ Although the majority of patients with NIDDM are insulin resistant, it is undecided whether the primary molecular defect lies within the insulin signal transduction pathway or in β-cell insulin secretion.^10,11

1.2 Animal Models of Diabetes

Animal models featuring physiological and pathological changes characteristic of each diabetes subtype are important to understand this complex disease better and to propose potential treatments. For example, specific etiological factors and/or genetic backgrounds can be selected and combined to produce a particular type of experimental diabetes, allowing the researcher to explore particular biochemical or anatomical alterations. In this way, animal models can provide a means to study disturbances found in human diabetes.

1.2.1 NIDDM Animal Models

The genetic NIDDM models are produced through selective breeding, spontaneous mutations, or genetic engineering. Some examples include the db/db mouse, ob/ob mouse, KK mouse, NZO mouse, fa/fa Zucker rat, and fa/fa diabetic Zucker rat. Most of these models demonstrate various degrees of glycemia, insulinemia, and obesity. Chemically induced NIDDM is obtained through injection of agents that produce the desired pathology. The most commonly used agent is streptozotocin (STZ). A mild and stable form of diabetes, resembling Type II human diabetes, is produced by a single dose of STZ (90 mg/kg i.v.) in 2-day-old neonatal rats.¹² The induced β-cell injury is followed by limited regeneration, primarily as a result of ductal budding rather than mitosi...